Prostate cancer is the most common cancer found in men and it is the second leading cause of death among men who die from cancer. By the age of 50, very few men have symptoms of prostate cancer, yet some precancerous or cancer cells may be present. More than half of all American men have some cancer in their prostate glands by the age of 80. Most of these cancers never pose a problem. See, National Cancer Institute Understanding Prostate Changes: A Health Guide for Men (http://wwwdotcancerdotgov/types/prostate/understanding-prostate-changes) current website guide Jan. 26, 2016. The American Cancer Society's estimates for prostate cancer in the United States for 2015 are approximately 220,800 new cases of prostate cancer; and 27,540 deaths from prostate cancer. See, American Cancer Society Prostate Cancer Guide (Ref: http://wwwdotcancerdotorg/acs/groups/cid/documents/webcontent/003134-pdf.pdf.) In 2012, the World Health Organization (WHO) estimated that 1.1 million men worldwide were diagnosed with prostate cancer (Ref: World Health Organization Prostate Cancer Fact Sheet. See, GloboCan 2012: Estimated Cancer Incidence, Mortality and Prevalence Worldwide in 2012. (http://globocandotiarcdotfr/Pages/fact_sheets_cancer.aspx)). That number was 15% of all cancers diagnosed in men. Also in 2012, WHO estimated that there were 307,000 deaths representing 6.6% of total men cancer deaths.
To illustrate such disease, there is depicted, in FIGS. 1 and 2, in cross-sectional view, a prostate 10 in proximity to other organs and anatomical structures, and how a cancerous growth within the prostate progresses through Stages I, II, III and IV. As shown in FIG. 1, the prostate is located just below the bladder 40 and in front of the rectum 50. The prostate 10 further surrounds a portion of the urethra 60 and further produces seminal fluid that nourishes and transports sperm as part of the male reproductive system. The progression of prostate cancer, like other forms of cancer, is characterized by four categories of staging that describe the local extent of a prostate tumor, ranging from Stage I or T1 to Stage IV or T4. With respect to Stage I, the tumor 20 typically cannot be felt or even seen with imaging equipment, such as transrectal ultrasound. Although highly ideal, the detection of cancer at such stage is considered almost accidental and is typically incidental to a separate transurethral resection of the prostate (TURP). Detection at such stage can also occur by needle biopsy performed as a result in increased prostate specific antigen (PSA), discussed more fully below.
Stage II is characterized as becoming enlarged to the point where the cancer 20 can be felt per a digital rectal exam (DRE) or can be seen with imaging such as transrectal ultrasound. The cancer 20 at such stage however, continues to be confined to the prostate gland 10.
In Stage III, the cancer 20 has grown outside of the prostate 10 and may have further grown into the seminal vesicle 30. In Stage IV, the cancer 20 has grown into tissue adjacent to the prostate (i.e., other than the seminal vesicles) and can extend into such structures such as the urethral sphincter, rectum 50, bladder 40 and/or the wall of the pelvis.
The treatment of prostate cancer can vary significantly depending on factors such as how fast the cancer is growing, how much it has spread, the patient's overall health, and the benefits and potential side effects of treatment. As is true for virtually all types of cancers, early detection is always preferred, with the treatment options available having substantially fewer side effects and significantly greater patient outcome compared to detection at later stages. Given the anatomical positioning of the prostate, however, coupled with numerous drawbacks associated with the accurate diagnosis of prostate cancer, the ability to detect prostate cancer at its earliest stages is elusive and well-known to result in the implementation of harmful, sub-optimal care, as discussed below.
I. Disadvantages Associated with Current Prostate Cancer Screening Methods
Management and treatment of prostate cancer is limited by access to an adequate sample of prostate tissue. See, Presti, J. Prostate Biopsy: Current Status and Limitations. Rev Urol. 2007, Summer, 9(3): 93-98. In this regard, the definitive diagnosis of prostate cancer is hampered by the limitations of acquiring prostate gland tissue using an invasive surgical procedure known as a prostate core needle biopsy. See, Shariat et. al. Using Biopsy to Detect Prostate Cancer. Reviews in Urology, 2008 Fall; 10(4): 262-280; and Taneja, et al. AUA/Optimal Techniques of Prostate Biopsy and Specimen Handling: White Paper for the American Urological Association, Inc. in https://wwwdotauanetdotorg/common/pdf/education/clinical-guidance/Prostate-Biopsy-WhitePaper.pdf as of Jan. 26, 2016. Specifically, such biopsy procedure is typically performed by a physician using transrectal ultrasound to visualize the prostate gland while a hollow needle is inserted through the wall of the rectum into the prostate gland. As the needle penetrates prostate tissue, a core of tissue forms inside the needle. When this needle is retracted from the prostate, the tissue core is expelled from the needle and mounted on a microscope slide for examination. Only tissue along the path of the needle can be examined. This procedure is repeated between 8 to 18 times (12 on average) to acquire tissue biopsy samples from multiple regions of the prostate. Local anesthesia is typically injected into the region adjoining the prostate to reduce pain associated with the biopsy procedure. Antibiotics are also administered to reduce the high infection risk associated with wounds near the rectum.
Based upon estimates of 1.3 million prostate biopsy procedures performed in the United States and an average of 12 cores per biopsy, approximately 15 million core biopsy specimens are collected and examined in the United States annually. More than 10 million (˜70%) of these biopsies are determined to be negative for prostate cancer. See, Chin et al., Is Repeat Biopsy for Isolated High-Grade Prostatic Intraepithelial Neoplasia Necessary? Rev Urology 2007; 9(3): 124-131. Due to physical limitations of the prostate core biopsy, there are more that 3 million false negative biopsies reported presumably resulting from failure of the needle to pass through cancer tissue. Many men with negative biopsy results are placed on active surveillance and will undergo second and third biopsy procedures due to persistent indications for repeat biopsy. As is recognized, a key cause for this excessive false negative rate is the limited needle path inherent to core needle biopsy procedures.
When the prostate core biopsy procedure is examined closely, it is apparent that small tumors are easily missed and will continue to flourish undetected and untreated. Also contributing to this failure to detect tumors is the small percentage of prostate tissue sampled by the biopsy procedure. The majority of prostate core biopsies are performed using an 18 gauge needle. Such biopsy needle produces a prostate tissue core with a maximum diameter of 0.84 mm and a typical length of 12 mm. See, Obek et al., Core length in prostate biopsy: size matters. J Urol. 2012 June; 187(6): 2015-5. An average prostate tissue volume of 8 microliters is acquired with each core. Based on an average of 12 cores per procedure, an estimated total of 0.096 milliliters of prostate tissue is acquired per procedure. See, Mustafa et al., When prostate cancer remains undetectable: The dilemma, Turkish J Urol 2015; 41(1): 32-8. Approximately 8 microliters per core×12 cores=96 microliters (0.096 mL). Adult male prostate tissue volumes, however, range between 25 and 50 mL. Thus, the percentage of total prostate tissue volume acquired by biopsy ranges from 0.384% to 0.2% of total prostate volume and after mounting and sectioning the cores for microscopic examination, less than 0.01% of the whole prostate tissue volume is examined.
Moreover, the biopsy procedure accesses the prostate through the rectum whereby the posterior prostate is most easily accessible to the biopsy apparatus. Hence a sampling bias exists and anterior tumors (located anterior to the urethra) require significantly more biopsy sessions than posterior tumors. See, Jones, Managing Patients Following a Negative Prostate Biopsy, Renal and Urology News 2011 Feb. 1. In this regard, and as illustrated in FIG. 5 (showing another aspect of the invention discussed herein), tumor 20 is situated in a deep, anterior position located at an opposed end where the prostate could otherwise be accessed through the rectum. As a consequence, even to the extent needle biopsies could access and detect the presence of cancerous tissue, such approach is only as effective as the entirety of the random sampling made about prostate organ, which needs to be sufficiently sampled completely thereabout rather than just not in the more easily accessed areas. Tumor 20 in FIG. 5 depicts how detecting such a tumor is problematic.
There can likewise be significant discomfort and medical risk associated with prostate core needle biopsies. Bleeding, antibiotic resistant infection/sepsis, urine retention, and tumor seeding (i.e., dislodging of tumor cells into tissue fluid or the circulation) are all well-known drawbacks associated with such procedure. See, e.g., US Preventative Services Task Force, Final Recommendation Statement Prostate Cancer: Screening, May 2012, K. Shyamala, et al., Risk of tumor cell seeding through biopsy and aspiration cytology, Journal of International Society of Preventive & Community Dentistry 2014 January-April; 4(1): 5-11); Volanis, et al., Incidence of needle-tract seeding following prostate biopsy for suspected cancer: a review of the literature, BJU Int. 2015 M; 115(5): 698-704); and Gonzales et al., AUA/SUNA White Paper on the Incidence, Prevention and Treatment of Complications Related to Prostate Needle Biopsy, American Urological Association Education and Research, Inc., 2012. Taken together, the medical risk, poor sensitivity, and patient discomfort, the prostate core biopsy procedure is a less than ideal active surveillance tool that is limited to annual or semi-annual use. Presently, there is a need for less invasive diagnostic methods to examine the prostate for the presence of prostate cancer.
As a potential diagnostic substitute, biomarkers have long been proposed as a non-invasive surveillance alternative to core needle biopsy. Specifically, non-invasive or minimally invasive diagnostic methods have been developed as indicators for a prostate core biopsy. Generally, these methods rely on detection of extracellular biomarkers present in body fluids or blood. See, Truong et al., Towards the Detection of Prostate Cancer in Urine: A Critical Analysis, J Urol. 2013 February; 189(2): 422-429. The biomarker data is typically interpreted against the result of a digital palpation through the rectum (digital rectal examine or DRE). The most common biomarker used for this purpose is prostate specific antigen (PSA). The link between prostate cancer and elevated (above normal range) levels of PSA as measured in human serum was first published in 1979. Since the discovery of PSA, many alternatives to PSA have been proposed and deployed clinically. A complete review of biomarkers for prostate cancer is disclosed in Velonas V., et al., Current Status of Biomarkers for Prostate Cancer, International Journal of Molecular Science, 2013 June; 14(6): 11034-11060, and incorporated herein by reference.
Unfortunately, despite the availability of multiple biomarkers relating to prostate cancer, none can match the unequivocal specificity of skilled examination of prostate tissue by a pathologist. Moreover, biomarker indications of prostate cancer are always confirmed by tissue biopsy prior to treatment and management of the patient and the data supporting this standard of care are overwhelming. In this regard, no biomarker has replaced PSA/DRE as the standard of care for prostate cancer surveillance and at best biomarkers serve as a surrogate for examining the cell type presumed to be associated with prostate cancer. As such, biomarkers cannot achieve specificity equivalent to interrogation of the physical prostate cell. Hence, tissue biopsy prevails as the definitive diagnostic method.
In fact, despite the belief that biomarkers may offer a less invasive method of patient management, data shows that a great deal of patient harm is associated with the use of biomarkers in patient management for prostate cancer. Along these lines, convincing evidence demonstrates that the PSA test often produces false-positive results, with reports that approximately 80% of positive PSA test results are false-positive when cutoffs between 2.5 and 4.0 μg/L are used. There is also adequate evidence that false-positive PSA test results are associated with negative psychological effects, including persistent worry about prostate cancer. Men who have a false-positive test result are more likely to have additional testing, including one or more biopsies in the following year than those who have a negative test result and over ten years, approximately 15% to 20% of men will have a PSA test result that triggers a biopsy, depending on the PSA threshold and testing interval used. Indeed, in addition to the findings discussed above, recent evidence from a randomized trial of treatment of screen-detected cancer indicates that roughly one third of men who have prostate biopsy experience pain, fever, bleeding, infection, transient urinary difficulties, or other issues requiring clinician follow-up that the men consider a “moderate or major problem” with approximately 1% requiring hospitalization.
II. Harms Related to Treatment of Screen-Detected Cancer
Adequate evidence shows that nearly 90% of men with PSA-detected prostate cancer in the United States have early treatment with surgery, radiation, or androgen deprivation therapy. Adequate evidence shows that up to 5 in 1000 men will die within 1 month of prostate cancer surgery and between 10 and 70 men will have serious complications but survive. Radiotherapy and surgery result in long-term adverse effects, including urinary incontinence and erectile dysfunction in at least 200 to 300 of 1000 men treated with these therapies. Radiotherapy is also associated with bowel dysfunction.
Some clinicians have used androgen deprivation therapy as the primary therapy for early-stage prostate cancer, particularly in older men, despite the fact such an approach is not a U.S. Food and Drug Administration (FDA)-approved indication and has not been shown to improve survival in localized prostate cancer. Adequate evidence shows that androgen deprivation therapy for localized prostate cancer is associated with erectile dysfunction (in approximately 400 of 1000 men treated), as well as gynecomastia and hot flashes.
As discussed above, there is convincing evidence that PSA-based screening leads to substantial over-diagnosis of prostate tumors. As a consequence, there is a high propensity for physicians and patients to elect to treat most cases of screen-detected cancer, notwithstanding the current inability to distinguish tumors that will remain indolent from those destined to be lethal. Thus, many men are being subjected to the harms of treatment of prostate cancer that will never become symptomatic. Even for men whose screen-detected cancer would otherwise have been later identified without screening, most experience the same outcome and are, therefore, unnecessarily subjected to the harms of treatment for a much longer period of time. Such PSA-based screening for prostate cancer has resulted in considerable overtreatment and its associated harms, and the United States Preventative Services Task Force (USPSTF) has considered the magnitude of these treatment-associated harms to be at least moderate. The fact that approximately 70% of prostate core biopsy results are negative also indicates that current non-invasive indications for biopsy (typically elevated PSA and DRE) are not specific for prostate cancer and cause many men to undergo unnecessary biopsy procedures and endure the pain and discomfort associated herewith, as previously discussed.
III. Attempts to Diagnose Prostate Cancer Via Detection of Free Cells
The use of exfoliated prostatic epithelial cells in semen and urine to detect prostate cancer has been reported. See, e.g., Couture, et. al. The isolation and identification of exfoliated prostate cells from human semen. Acta Cyto., 1980 May-June; 24(3): 262-267; Barren et al. Method for Identifying Prostate Cells in Semen Using Flow Cytometry, The Prostate, 1998 August; 36:181-188, Andrade-Rocha. Assessment of exfoliated prostate cells in semen: relationship with the secretory function of the prostate. Several researchers have reported, however, that attempts to detect prostate tumor cells in these specimens routinely is thwarted by unacceptably low sensitivities due to the rare numbers of prostate cells found in the urine. See, Nakai et al., Photodynamic diagnosis of shed prostate cancer cells in voided urine treated with 5-aminolevulinic acid, BMC Urology 2014, 14:59.
In efforts to enhance diagnostic sensitivity, the prior art has employed cell sorting methods or immunomagnetic isolation of prostate cells to enrich the prostate cell population. However, using these cell concentration techniques also failed to provide adequate cell numbers and diagnostic sensitivity. Studies have reported sensitivities ranging between 15% and 30% even when DRE is used to exfoliate prostate cells prior to collection of voided urine. See, Fujita K, Pavlovich C P, Netto G J, et al., Specific detection of prostate cancer cells in urine by multiplex immunofluorescence cytology, Hum Pathol. 2009; 40:924, [PubMed: 19368959]. Furthermore, when found cytologically, PCa cells in the urine occur almost exclusively in patients with high grade or advanced cancers (Tyler K L, Selvaggi S M., Morphologic features of prostatic adenocarcinoma on ThinPrep® urinary cytology, Diagn Cytopathol. 2011; 39:101. [PubMed: 20146303]).
Although exfoliated prostatic epithelial cells can be acquired by non-invasive or minimally invasive sample collection methods, the potential for use as a reliable diagnostic method for detection of prostate cancer has not been realized due to the low numbers of prostate cells available even following prostatic massage. Indeed, despite efforts to develop devices operative to facilitate collection of samples that seek to improve the probabilities that target cells of interest can be isolated and detected, such devices have proven ineffective. Exemplary of such devices include several intra-urethral devices that are operative to extend into the prostatic urethra and obtain samples in proximity thereto and include those disclosed in Published United States Patent Application Number US2002/0026209, filed in the name of Hung, entitled METHOD AND DEVICE FOR OBTAINING PROSTATIC MATERIAL, published Feb. 28, 2002; Published United States Patent Application Number US2005/0054994, filed in the name of Cioanta, et al., entitled CATHETERS WITH SUCTION CAPABILITY AND RELATED METHODS AND SYSTEMS FOR OBTAINING BIO-SAMPLES IN VIVO, published Mar. 10, 2005; and Published United States Patent Application Number US2011/0208022, filed in the name of Brawer, et al., entitled DEVICE AND METHODS FOR SAMPLING PROSTATIC FLUID, published Aug. 25, 2011, the teachings of all of which are expressly incorporated herein by reference.
Among the drawbacks associated with all such devices and collection techniques using the same include the inability to selectively deploy such devices in a manner that maximizes the potential to capture the target cells of interest at the target prostatic urethral site. Indeed, the use of such devices is completely random and there is no way to determine, and much less selectively deploy such devices at a time when the probability of collecting target cancer cells of interest is greatly enhanced. There is likewise no type of means for maximizing the probability that the target cancer cells will be in the prostatic urethra, as opposed to being located deep within the prostate, as illustrated in FIG. 5, and thus incapable of being accessed by such devices. Accordingly, despite being slightly less invasive, such devices at best only provide a moderately increased chance of detecting the target cancer cells of interest.
A yet further approach is disclosed in published United States Patent Application Number US2009/0263799, filed in the name of Smith et al., entitled ASSAY FOR PROSTATE CANCER, published Oct. 22, 2009. The Smith application proposes the use of Expressed Prostatic Secretion (EPS) as specimens for the detection of prostate cancer. More specifically, various and multiple biomarkers present in the EPS sample are used to determine whether the patient has prostate cell proliferative disorder (prostate cancer, prostate carcinoma, or prostate neoplasm). Smith's method relies on the presumption that prostate cells are the source (origin) of the biomarkers; however, Smith does not include an enumeration or examination of intact prostatic epithelial cells allegedly the source of the biomarkers. Smith likewise does not anticipate the use of an exfoliating agent to increase the sensitivity of the biomarker assay.
In summary, prior art non-invasive and minimally invasive diagnostic methods rely on the supposition that the clinical specimen (peripheral blood, urine, semen, expressed prostatic secretions, etc.) contains a biomarker, genetic material, and/or cells originating from the prostate. The success or failure of prior art detection techniques hinges on the presence of the biomarker, genetic material, or prostate cells in quantities sufficient for detection. The prior art, however, is completely deficient in any sort of structured methodology that can substantially increase the probability that the sought after biomarker, genetic material, or prostate cells can be increased in population and density so as to more easily, readily and accurately assess a patient's condition.
Accordingly, there is an overwhelming need in the art for methods that can be deployed to enhance the ability to collect and detect target prostate cells in a manner that is reliable and readily reproducible, and enables the collected cells to be subsequently tested or otherwise utilized for a wide variety of applications. There is a further need in the art for such methodologies that substantially minimize, if not eliminate, the pain, complexity and numerous other drawbacks associated with needle biopsy procedures while at the same time providing substantially more accurate and sensitive sampling that can detect the presence of a biomarker, genetic material or prostate cell presence to a far greater degree than prior art procedures. Still further, there is a need in the art for such methodologies that are minimally invasive, substantially minimize patient discomfort, have no side effects associated with risk of infection, scarring and debilitating side effects associated with conventional testing and that can be readily deployed on demand without any type of specialized medical equipment, any type of procedure that must be performed by highly trained medical personnel or is otherwise associated with a high cost medical procedure.